Beta-agonist compounds comprising nitric oxide donor groups and reactive oxygen species scavenger groups and their use in the treatment of respiratory disorders

• US 7,378,438 B2
• Filed: 04/15/2003
• Issued: 05/27/2008
• Est. Priority Date: 04/19/2002
• Status: Expired due to Fees

• Current Assignee: Yissum Research Development Company of the Hebrew University of Jerusalem Ltd. (Hebrew University of Jerusalem)
• Original Assignee: Yissum Research Development Company of the Hebrew University of Jerusalem Ltd. (Hebrew University of Jerusalem)
• Inventors: Haj-Yehia, Abdullah Ibrahim
• Primary Examiner(s): Anderson; Rebecca L
• Assistant Examiner(s): NOLAN, JASON MICHAEL
• Application Number:
  US10/512,024
• Publication Number:
  US 20050228184A1
• Time in Patent Office: 1,869 Days
• Field of Search: 514/414, 514/416, 548/467, 548/470
• US Class Current: 514/416
• CPC Class Codes: A61K 31/385 having two or more sulfur atoms in the same ring
• CPC Class Codes: A61K 31/4035 Isoindoles, e.g. phthalimide
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 209/44 Iso-indoles; Hydrogenated iso-indoles
• CPC Class Codes: C07D 339/04 having the hetero atoms in positions 1 and 2, e.g. lipoic acid
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links

Abstract

The present invention relates to multifunctional β-agonist compounds comprising a reactive oxygen species scavenger group and a nitric oxide donor, and their use for the treatment of respiratory diseases involving airway obstruction, such as asthma and chronic bronchitis. The invention further relates to methods and devices for administering the compounds.

Claims

1. A multifunctional β

-agonist compound having reactive oxygen species (ROS) scavenger groups and nitric oxide (NO) donor groups being ROS scavenger and NO donor of Formula 1;

2. A β

-agonist compound according to claim 1, wherein said saturated heterocycle is selected from the group consisting of pyrrolidine, oxazolidine, thiazolidine, tetrahydro 1,3-oxazine, 1,3-dioxane, piperidine, 3-thiapiperidine, and 1,3-thiazine.

3. A β

-agonist compound according to claim 1, wherein the nitroxide free radical is a heterocyclyl moiety having the nitrogen atom within a 5-, 6- or 7-membered ring which optionally contains another heteroatom selected from oxygen and sulfur at position beta to the nitrogen, and which is substituted with methyl or ethyl at positions alpha to the nitrogen.

4. The β

-agonist compound of claim 3, wherein said heterocyclyl moiety is linked to the β

-agonist moiety via sharing of 1 to 2 atoms, or via a linker.

5. A n-agonist compound according to claim 1, wherein said ROS scavenger group is selected from the group consisting of the following moieties:

6. A β

-agonist compound according to claim 1, wherein R² is selected from the following structures;

7. A β

-agonist compound according to claim 1 having the formula;

8. A multifunctional β

-agonist compound according to claim 1 having one of the following structures;

9. A process of preparing an agonist according to claim 1 being a compound of the formula:

10. A process according to claim 9, wherein said epoxide is prepared from N-benzylphthalimide.

11. A process according to claim 9, further comprising converting —

SH groups to —

SNO groups in the presence of HCl and NaNO₂.

12. A composition comprising a multifunctional β

-agonist compound of claim 1, or a salt thereof or a solvate thereof or an optical isomer thereof, for use as a medicament.

13. A pharmaceutical composition comprising a β

-agonist compound of any one of claims 1 to 8, or a salt thereof or a solvate thereof or an optical isomer thereof.

14. A pharmaceutical composition according to claim 13, further comprising carriers, adjuvants, and excipients.